Document Detail


Regulated vesicular trafficking of specific PCDH15 and VLGR1 variants in auditory hair cells.
MedLine Citation:
PMID:  23035094     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Usher syndrome is a genetically heterogeneous disorder characterized by hearing and balance dysfunction and progressive retinitis pigmentosa. Mouse models carrying mutations for the nine Usher-associated genes have splayed stereocilia, and some show delayed maturation of ribbon synapses suggesting these proteins may play different roles in terminal differentiation of auditory hair cells. The presence of the Usher proteins at the basal and apical aspects of the neurosensory epithelia suggests the existence of regulated trafficking through specific transport proteins and routes. Immature mouse cochleae and UB/OC-1 cells were used in this work to address whether specific variants of PCDH15 and VLGR1 are being selectively transported to opposite poles of the hair cells. Confocal colocalization studies between apical and basal vesicular markers and the different PCDH15 and VLGR1 variants along with sucrose density gradients and the use of vesicle trafficking inhibitors show the existence of Usher protein complexes in at least two vesicular subpools. The apically trafficked pool colocalized with the early endosomal vesicle marker, rab5, while the basally trafficked pool associated with membrane microdomains and SNAP25. Moreover, coimmunoprecipitation experiments between SNAP25 and VLGR1 show a physical interaction of these two proteins in organ of Corti and brain. Collectively, these findings establish the existence of a differential vesicular trafficking mechanism for specific Usher protein variants in mouse cochlear hair cells, with the apical variants playing a potential role in endosomal recycling and stereocilia development/maintenance, and the basolateral variants involved in vesicle docking and/or fusion through SNAP25-mediated interactions.
Authors:
Marisa Zallocchi; Duane Delimont; Daniel T Meehan; Dominic Cosgrove
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural    
Journal Detail:
Title:  The Journal of neuroscience : the official journal of the Society for Neuroscience     Volume:  32     ISSN:  1529-2401     ISO Abbreviation:  J. Neurosci.     Publication Date:  2012 Oct 
Date Detail:
Created Date:  2012-10-04     Completed Date:  2013-01-17     Revised Date:  2013-07-11    
Medline Journal Info:
Nlm Unique ID:  8102140     Medline TA:  J Neurosci     Country:  United States    
Other Details:
Languages:  eng     Pagination:  13841-59     Citation Subset:  IM    
Affiliation:
Boys Town National Research Hospital, Omaha, Nebraska 68131, USA.
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MeSH Terms
Descriptor/Qualifier:
ADP-Ribosylation Factor 1 / analysis
Animals
Brain Chemistry
Cadherins / biosynthesis,  genetics,  metabolism*
Cell Compartmentation
Cell Differentiation
Cell Polarity / physiology*
Disease Models, Animal
Gene Knockdown Techniques
Hair Cells, Auditory / metabolism,  ultrastructure*
Immunoprecipitation
Mice
Mice, Neurologic Mutants
Mutation
Organ of Corti / chemistry,  ultrastructure
Protein Interaction Mapping
Protein Precursors / biosynthesis,  genetics,  metabolism*
Protein Transport / drug effects
RNA Interference
Receptors, G-Protein-Coupled / biosynthesis,  chemistry,  genetics,  metabolism*
Structure-Activity Relationship
Synaptosomal-Associated Protein 25 / analysis,  chemistry,  metabolism
Transport Vesicles / chemistry,  physiology*
Usher Syndromes / metabolism
rab5 GTP-Binding Proteins / analysis
Grant Support
ID/Acronym/Agency:
5 P20 RR018788-08/RR/NCRR NIH HHS; 5P20RR016469/RR/NCRR NIH HHS; 8P20GM103427/GM/NIGMS NIH HHS; R01 DC004844/DC/NIDCD NIH HHS; R01 DC004844/DC/NIDCD NIH HHS
Chemical
Reg. No./Substance:
0/Cadherins; 0/Mass1 protein, mouse; 0/Pcdh15 protein, mouse; 0/Protein Precursors; 0/Receptors, G-Protein-Coupled; 0/Snap25 protein, mouse; 0/Synaptosomal-Associated Protein 25; EC 3.6.5.2/ADP-Ribosylation Factor 1; EC 3.6.5.2/rab5 GTP-Binding Proteins
Comments/Corrections

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